# Missense Variants in the Second Transmembrane Domain of TMEM17 Disrupt Its Stability and Function and Lead to a Wide Phenotypic Spectrum of Ciliopathies

## TL;DR

Missense variants in TMEM17 disrupt its function in cilia, causing a range of ciliopathy disorders from mild to severe.

## Contribution

Expands TMEM17's phenotypic spectrum to include Meckel syndrome and confirms its role as a ciliopathy gene.

## Key findings

- TMEM17 missense variants cause destabilization and mislocalization of the protein.
- Variants disrupt ciliary function and Sonic Hedgehog signaling.
- TMEM17 is confirmed as a key gene in ciliopathies with a wide phenotypic range.

## Abstract

Ciliopathies are rare genetic disorders characterized by significant genetic and phenotypic variability. Over 140 proteins localized to primary cilia, which are sensory organelles essential for vertebrate development, are implicated. TMEM17 encodes a transmembrane protein at the ciliary transition zone and was previously proposed as a potential ciliopathy gene, based on reports of individuals from two families with orofaciodigital syndrome type 6 (OFD6) and Joubert syndrome (JS). Here, we report two unrelated fetuses with occipital encephalocele, polydactyly, and kidney cysts, in whom exome sequencing identified a founder homozygous missense variant (Arg94Trp) in TMEM17, affecting a highly conserved residue. This expands the TMEM17‐associated phenotypic spectrum to include Meckel syndrome (MKS). Comprehensive functional analyses of all known TMEM17 variants, using patient tissues/cells and a
C. elegans
model system, demonstrate a loss‐of‐function mechanism. Our study reveals severe functional consequences, including TMEM17 destabilization and mislocalization, anomalies in cilium composition and function, and abrogation of Sonic Hedgehog signaling. These experiments confirm the pathogenicity of all TMEM17 variants and underscore its essential role at the ciliary transition zone. Collectively, our findings establish TMEM17 as a bona fide ciliopathy gene, associated with a wide phenotypic spectrum ranging from viable syndromes (OFD6 and JS) to a fetal‐lethal condition (MKS).

Missense variants in TMEM17 disrupt its localization and function at the ciliary transition zone, leading to a wide range of ciliopathy phenotypes, from OFD6 and Joubert syndromes to Meckel syndrome.